This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This proposal consists of two projects: Project 1. PNA solution structure. The objectives of this proposal are to characterize the structure and dynamics of PNA/PNA and DNA/DNA double helices in solution, with different metal substitutions. The obtained structures will be used as input to semi-empirical and ab initio electron transfer (ET) studies, in order to study the effect of sequence, structure, flexibility, solvent and charge on ET. Our long-term goal is to design and synthesize molecular systems based on metal-peptide nucleic acids (metal-PNA) duplexes, which allow the precise control of electronic flow. This project is a fruitful collaboration with Prof. Catalina Achim, who synthesizes metal-containing PNA, Prof. David Waldeck and Eric Borguet, who conduct electron transfer experiments, and Prof. David Beratan, who will use ab-initio and semi-empirical methods to calculate electron transfer rates. Project 2. Mutant RT-NNRTI complexes. The long term goal of our HIV-1 reverse transcriptase (RT) research is to design new anti-AIDS drugs, more effective against wild-type and mutant RT. We have recently completed a study of the interactions of several drugs (including the latest generation, more effective, DAPYs) in the binding pocket of wild-type RT (as detailed in the Progress Report). In order to propose modifications to these drugs, we need to ensure that our conclusions are also valid in the presence of mutant RT. The proposed modifications should, then, be effective against both wild-type and commonly occurring mutations. The objectives of the proposed research are to understand the interactions with mutant RT Lys103Asn. The proposed drug derivatives will be synthesized in the laboratory of our collaborator, Prof. Brin.